Pub Date : 2026-03-01Epub Date: 2026-03-04DOI: 10.1016/j.jtho.2025.12.003
Ivy Riano MD, Konstantin H. Dragnev MD
{"title":"Advancing Frontline Therapy in Metastatic NSCLC: Lessons From EVOKE-02 on Antibody–Drug Conjugates–Immunotherapy Combination","authors":"Ivy Riano MD, Konstantin H. Dragnev MD","doi":"10.1016/j.jtho.2025.12.003","DOIUrl":"10.1016/j.jtho.2025.12.003","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103533"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-04DOI: 10.1016/S1556-0864(26)00050-X
{"title":"Board of Directors","authors":"","doi":"10.1016/S1556-0864(26)00050-X","DOIUrl":"10.1016/S1556-0864(26)00050-X","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103597"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147387850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-14DOI: 10.1016/j.jtho.2025.11.006
Hongcheng Zhu MD, PhD , Said Al Saifi MD , Houda Bahig MD, PhD , Alissa Cooper MD , Fernando Conrado Abrão MD , Luis Corrales MD , Corinne Faivre-Finn PhD , Andrea Riccardo Filippi MD , Bailey Fitzgerald MD , Divya Khosla MD , Vincent K. Lam MD , Xiuning Le MD, PhD , Vanessa Menezes MD , Tom Newsom-Davis FRCP, PhD , Angel Qin MD , Paul Martin Putora MD, PhD, HOCH , Pablo Munoz-Schuffenegger MD , Shankar Siva PhD, M.B.B.S., FRANZCR , Nathan Y. Yu MD , Alexander V. Louie MD, PhD
Introduction
Stage III NSCLC is a heterogeneous disease with multiple curative and palliative treatment options. Surgery and radiotherapy are the primary local treatment modalities, and their use is guided by the principals of tumor resectability and patient operability. Neoadjuvant and adjuvant immunotherapies have changed the patterns of multidisciplinary management of stage III NSCLC.
Methods
On behalf of the Multidisciplinary Clinical Science Committee and Advanced Radiotherapy Technology Subcommittee of the International Association for the Study of Lung Cancer, we present five cases representing challenging scenarios for discussion.
Results
The first is strategies for optimizing staging before curative intent, particularly the role of endobronchial ultrasound. The second focuses on the role of targeted therapies in the curative-intent chemoradiotherapy paradigm. The third evaluates treatment approaches for elderly or comorbid patients, specifically the choice between radiotherapy and systemic therapy. The fourth considers the management of patients who do not undergo surgery after neoadjuvant systemic therapy. The fifth concerns the role of adjuvant radiotherapy after neoadjuvant therapy and surgery.
Conclusions
Herein, we present a review of challenging clinical scenarios often encountered in thoracic multidisciplinary tumor boards.
{"title":"Radiotherapy for Unresectable Locally Advanced NSCLC: A Practical Multidisciplinary Approach to Challenging Scenarios From the International Association for the Study of Lung Cancer Advanced Radiation Technology Subcommittee","authors":"Hongcheng Zhu MD, PhD , Said Al Saifi MD , Houda Bahig MD, PhD , Alissa Cooper MD , Fernando Conrado Abrão MD , Luis Corrales MD , Corinne Faivre-Finn PhD , Andrea Riccardo Filippi MD , Bailey Fitzgerald MD , Divya Khosla MD , Vincent K. Lam MD , Xiuning Le MD, PhD , Vanessa Menezes MD , Tom Newsom-Davis FRCP, PhD , Angel Qin MD , Paul Martin Putora MD, PhD, HOCH , Pablo Munoz-Schuffenegger MD , Shankar Siva PhD, M.B.B.S., FRANZCR , Nathan Y. Yu MD , Alexander V. Louie MD, PhD","doi":"10.1016/j.jtho.2025.11.006","DOIUrl":"10.1016/j.jtho.2025.11.006","url":null,"abstract":"<div><h3>Introduction</h3><div>Stage III NSCLC is a heterogeneous disease with multiple curative and palliative treatment options. Surgery and radiotherapy are the primary local treatment modalities, and their use is guided by the principals of tumor resectability and patient operability. Neoadjuvant and adjuvant immunotherapies have changed the patterns of multidisciplinary management of stage III NSCLC.</div></div><div><h3>Methods</h3><div>On behalf of the Multidisciplinary Clinical Science Committee and Advanced Radiotherapy Technology Subcommittee of the International Association for the Study of Lung Cancer, we present five cases representing challenging scenarios for discussion.</div></div><div><h3>Results</h3><div>The first is strategies for optimizing staging before curative intent, particularly the role of endobronchial ultrasound. The second focuses on the role of targeted therapies in the curative-intent chemoradiotherapy paradigm. The third evaluates treatment approaches for elderly or comorbid patients, specifically the choice between radiotherapy and systemic therapy. The fourth considers the management of patients who do not undergo surgery after neoadjuvant systemic therapy. The fifth concerns the role of adjuvant radiotherapy after neoadjuvant therapy and surgery.</div></div><div><h3>Conclusions</h3><div>Herein, we present a review of challenging clinical scenarios often encountered in thoracic multidisciplinary tumor boards.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103516"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-10-30DOI: 10.1016/j.jtho.2025.10.016
Martin Reck MD, PhD , Jyoti D. Patel MD, FASCO , Jhanelle E. Gray MD , Noemí Reguart MD, PhD , Manuel Cobo MD, PhD , José Fuentes Pradera MD , Enriqueta Felip MD, PhD , Federico Cappuzzo MD, PhD , Edward B. Garon MD, MS , Joel W. Neal MD, PhD , Sabeen Mekan MD , Farnoush Safavi MD, MBA, MHA , Nelumka Fernando MS , Marianna Zavodovskaya MS , Juliane M. Jürgensmeier PhD , Michael Chisamore PhD , Byoung Chul Cho MD, PhD
Introduction
Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate previously studied in patients with pretreated metastatic NSCLC (mNSCLC). Here, we report the results of EVOKE-02 (NCT05186974), a global, open-label, multicohort phase 2 study of SG plus pembrolizumab as first-line treatment in patients with mNSCLC.
Methods
Adult patients without prior systemic mNSCLC treatment, and no actionable genomic alterations, received SG 10 mg/kg intravenously on days 1 and 8 plus pembrolizumab 200 mg intravenously on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per independent review committee, and secondary end points included progression-free survival (PFS) and safety.
Results
As of data cutoff (June 3, 2024), there were 30 patients with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) more than or equal to 50% (cohort A) and 62 patients with PD-L1 TPS less than 50% (cohort B). ORR (95% confidence interval) was 66.7% (47.2–82.7) for cohort A and 29.0% (18.2–41.9) for cohort B. Median (95% confidence interval) PFS was 13.1 (6.7–not reached) months for cohort A and 7.0 (4.2–12.9) months for cohort B. Trop-2 expression did not correlate with greater clinical efficacy (PFS, ORR) from treatment with SG plus pembrolizumab. Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 70 patients (76.1%); the most common TEAE was neutropenia (17.4%). TEAEs leading to discontinuation of any study drug occurred in 25 patients (27.2%).
Conclusions
SG plus pembrolizumab demonstrated activity as treatment for mNSCLC, especially in patients with PD-L1 TPS more than or equal to 50%. AEs were manageable and consistent with the known safety profile of each individual agent.
{"title":"First-Line Sacituzumab Govitecan Plus Pembrolizumab in Metastatic NSCLC: PD-L1 TPS Less Than 50% and More Than or Equal to 50% Cohorts of the EVOKE-02 Study","authors":"Martin Reck MD, PhD , Jyoti D. Patel MD, FASCO , Jhanelle E. Gray MD , Noemí Reguart MD, PhD , Manuel Cobo MD, PhD , José Fuentes Pradera MD , Enriqueta Felip MD, PhD , Federico Cappuzzo MD, PhD , Edward B. Garon MD, MS , Joel W. Neal MD, PhD , Sabeen Mekan MD , Farnoush Safavi MD, MBA, MHA , Nelumka Fernando MS , Marianna Zavodovskaya MS , Juliane M. Jürgensmeier PhD , Michael Chisamore PhD , Byoung Chul Cho MD, PhD","doi":"10.1016/j.jtho.2025.10.016","DOIUrl":"10.1016/j.jtho.2025.10.016","url":null,"abstract":"<div><h3>Introduction</h3><div>Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate previously studied in patients with pretreated metastatic NSCLC (mNSCLC). Here, we report the results of EVOKE-02 (NCT05186974), a global, open-label, multicohort phase 2 study of SG plus pembrolizumab as first-line treatment in patients with mNSCLC.</div></div><div><h3>Methods</h3><div>Adult patients without prior systemic mNSCLC treatment, and no actionable genomic alterations, received SG 10 mg/kg intravenously on days 1 and 8 plus pembrolizumab 200 mg intravenously on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per independent review committee, and secondary end points included progression-free survival (PFS) and safety.</div></div><div><h3>Results</h3><div>As of data cutoff (June 3, 2024), there were 30 patients with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) more than or equal to 50% (cohort A) and 62 patients with PD-L1 TPS less than 50% (cohort B). ORR (95% confidence interval) was 66.7% (47.2–82.7) for cohort A and 29.0% (18.2–41.9) for cohort B. Median (95% confidence interval) PFS was 13.1 (6.7–not reached) months for cohort A and 7.0 (4.2–12.9) months for cohort B. Trop-2 expression did not correlate with greater clinical efficacy (PFS, ORR) from treatment with SG plus pembrolizumab. Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 70 patients (76.1%); the most common TEAE was neutropenia (17.4%). TEAEs leading to discontinuation of any study drug occurred in 25 patients (27.2%).</div></div><div><h3>Conclusions</h3><div>SG plus pembrolizumab demonstrated activity as treatment for mNSCLC, especially in patients with PD-L1 TPS more than or equal to 50%. AEs were manageable and consistent with the known safety profile of each individual agent.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103509"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-10-23DOI: 10.1016/j.jtho.2025.10.012
Monica F. Chen MD , Jake June-Koo Lee MD, PhD , Noura J. Choudhury MD , Angela B. Hui PhD , Mark Y. Jeng MD, PhD , Jennifer Zheng BS , Rania G. Aly MD, PhD , Neil Sielski MD , Linda Ahn BA , Amanda Pupo MA , Monica C. Nesselbush PhD , Isabel Jabara BS , Jessica A. Wilcox MD , Bianca D. Santomasso MD, PhD , Andrew L. Lin MD , Lauren Schaff MD , Jamie E. Chaft MD , Gregory J. Riely MD, PhD , Mark G. Kris MD , Andrea Arfe PhD , Helena A. Yu MD
Introduction
Despite improved central nervous system (CNS) disease control with osimertinib, 20% of patients will develop CNS progression. Amivantamab and lazertinib have demonstrated activity in patients with EGFR-mutant lung cancer. This trial evaluated amivantamab and lazertinib in patients with new or progressive CNS metastases after prior therapy (NCT04965090).
Methods
We evaluated amivantamab and lazertinib in two cohorts: patients with (1) brain metastases (BrM) or (2) leptomeningeal disease (LMD) diagnosed by cytology in patients with lung cancers with sensitizing EGFR-activating mutations or exon 20 insertions. The primary end point was composite best overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and Response Assessment in Neuro-Oncology brain metastases or Response Assessment in Neuro-Oncology leptomeningeal metastases. Secondary end points were toxicity, systemic ORR, CNS ORR, time on treatment, progression-free survival (PFS), CNS PFS, and overall survival.
Results
We treated 20 patients with BrM and 21 patients with LMD. Of the patients, 41% had EGFR del19, 37% L858R, 12% ex20ins, and 10% uncommon mutations. Median lines of prior therapy were 2 (range 1–7). The ORR by a combination of Response Evaluation Criteria in Solid Tumors and Response Assessment in Neuro-Oncology brain metastases/Response Assessment in Neuro-Oncology leptomeningeal metastases was 50% (95% confidence interval [CI], 27%–73%) for patients with BrM and 33% (95% CI, 15%–57%) for patients with LMD, respectively. The median PFS was 5.8 months (95% CI, 3.6–not reached [NR]) and 7.8 months (95% CI, 4.2–12.2) for the BrM and LMD cohorts, respectively. Median overall survival was 17.4 months (15.4–NR) in the BrM cohort and 14.4 months (8.9–NR) in the LMD cohort.
Conclusions
Amivantamab plus lazertinib has antitumor activity in patients with EGFR-mutant lung cancers who develop new or progressing BrM or LMD. This trial demonstrates the feasibility of including patients with LMD in prospective clinical trials.
背景：尽管奥西替尼改善了中枢神经系统（CNS）疾病控制，但20%的患者会出现中枢神经系统进展。阿米万他抗和拉泽替尼已经证明对egfr突变型肺癌患者有活性。该试验评估了阿米伐他单和拉泽替尼在既往治疗后新发或进展性中枢神经系统转移患者中的疗效（NCT04965090）。方法：我们在2个队列中评估阿米伐他单和拉泽替尼：1)脑转移（BrM）或2)肺癌患者的细胞学诊断为瘦脑膜病（LMD），这些患者有致敏的egfr激活突变或外显子20插入。主要终点是RECIST v 1.1和RANO-BM或-LM的综合最佳总有效率（ORR）。次要终点是毒性、全身ORR、CNS ORR、治疗时间（ToT）、无进展生存期（PFS）、CNS PFS和总生存期（OS）。结果：治疗BrM患者20例，LMD患者21例。41%的人有EGFR del19, 37%的人有L858R， 12%的人有ex20ins， 10%的人有罕见突变。既往治疗中位数：2（范围1-7）。对于BrM患者，RECIST和RANO-BM/RANO-LM联合治疗的ORR分别为50% （95% CI, 27-73%）和33% （95% CI, 15-57%）。BrM组和LMD组的中位PFS分别为5.8个月（95% CI 3.6-未达到（NR））和7.8个月（95% CI 4.2-12.2）。BrM组的中位生存期为17.4个月（15.4 nr）， LMD组的中位生存期为14.4个月（8.9 nr）。结论：Amivantamab+lazertinib对发生新的或进展中的脑或脑膜转移的egfr突变肺癌患者具有抗肿瘤活性。该试验证明了将LMD患者纳入前瞻性临床试验的可行性。
{"title":"Phase 2 Study of Amivantamab Plus Lazertinib in Previously Treated Patients With EGFR-Mutant Lung Cancers With Brain and Leptomeningeal Metastases","authors":"Monica F. Chen MD , Jake June-Koo Lee MD, PhD , Noura J. Choudhury MD , Angela B. Hui PhD , Mark Y. Jeng MD, PhD , Jennifer Zheng BS , Rania G. Aly MD, PhD , Neil Sielski MD , Linda Ahn BA , Amanda Pupo MA , Monica C. Nesselbush PhD , Isabel Jabara BS , Jessica A. Wilcox MD , Bianca D. Santomasso MD, PhD , Andrew L. Lin MD , Lauren Schaff MD , Jamie E. Chaft MD , Gregory J. Riely MD, PhD , Mark G. Kris MD , Andrea Arfe PhD , Helena A. Yu MD","doi":"10.1016/j.jtho.2025.10.012","DOIUrl":"10.1016/j.jtho.2025.10.012","url":null,"abstract":"<div><h3>Introduction</h3><div>Despite improved central nervous system (CNS) disease control with osimertinib, 20% of patients will develop CNS progression. Amivantamab and lazertinib have demonstrated activity in patients with <em>EGFR</em>-mutant lung cancer. This trial evaluated amivantamab and lazertinib in patients with new or progressive CNS metastases after prior therapy (NCT04965090).</div></div><div><h3>Methods</h3><div>We evaluated amivantamab and lazertinib in two cohorts: patients with (1) brain metastases (BrM) or (2) leptomeningeal disease (LMD) diagnosed by cytology in patients with lung cancers with sensitizing <em>EGFR-</em>activating mutations or exon 20 insertions. The primary end point was composite best overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and Response Assessment in Neuro-Oncology brain metastases or Response Assessment in Neuro-Oncology leptomeningeal metastases. Secondary end points were toxicity, systemic ORR, CNS ORR, time on treatment, progression-free survival (PFS), CNS PFS, and overall survival.</div></div><div><h3>Results</h3><div>We treated 20 patients with BrM and 21 patients with LMD. Of the patients, 41% had <em>EGFR</em> del19, 37% L858R, 12% ex20ins, and 10% uncommon mutations. Median lines of prior therapy were 2 (range 1–7). The ORR by a combination of Response Evaluation Criteria in Solid Tumors and Response Assessment in Neuro-Oncology brain metastases/Response Assessment in Neuro-Oncology leptomeningeal metastases was 50% (95% confidence interval [CI], 27%–73%) for patients with BrM and 33% (95% CI, 15%–57%) for patients with LMD, respectively. The median PFS was 5.8 months (95% CI, 3.6–not reached [NR]) and 7.8 months (95% CI, 4.2–12.2) for the BrM and LMD cohorts, respectively. Median overall survival was 17.4 months (15.4–NR) in the BrM cohort and 14.4 months (8.9–NR) in the LMD cohort.</div></div><div><h3>Conclusions</h3><div>Amivantamab plus lazertinib has antitumor activity in patients with <em>EGFR</em>-mutant lung cancers who develop new or progressing BrM or LMD. This trial demonstrates the feasibility of including patients with LMD in prospective clinical trials.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103505"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-17DOI: 10.1016/j.jtho.2025.11.010
Jessica S. Ross MD , Rohit Thummalapalli MD , Christopher A. Febres-Aldana MD , Daniel Muldoon MPH , Christina Falcon MPH , Amanda Pupo MA , Noura J. Choudhury MD , Guillherme Harada MD , Soo-Ryum Yang MD , Scott Eckert PhD , Francis M. Bodd MS , Jennifer L. Sauter MD , Chaitanya Bandlamudi PhD , Michael Berger PhD , Mark Y. Jeng MD, PhD , Michael Offin MD , Alexander Drilon MD , Mark G. Kris MD , Mark M. Awad MD, PhD , Helena Yu MD , Kathryn C. Arbour MD
Introduction
Methylthioadenosine phosphorylase (MTAP) deletions (dels) occur with CDKN2A dels in a subset of NSCLCs. These deletions have been associated with inferior survival in several tumor types, and they may be targetable by PRMT5 and MAT2A inhibitors through synthetic lethality. Their co-occurrence with oncogenic drivers including EGFR is underexplored.
Methods
We analyzed 4926 NSCLC tumors sequenced with MSK-IMPACT, a next-generation sequencing panel, and evaluated the incidence of MTAP dels with a copy number–based approach.
Results
Of 4926 NSCLC tumors, 475 (10%) harbored an MTAP del. Among 258 stage IV MTAP-del NSCLC tumors, 214 (83%) also had a co-occurring oncogenic driver alteration, including 123 (48%) with EGFR mutations. Baseline MTAP del was associated with shorter time to osimertinib monotherapy discontinuation (19.0 versus 24.9 mo, hazard ratio 1.8, confidence interval 1.02–3.15, p = 0.01) but did not statistically significantly affect overall survival (38.4 versus 40.5 mo, hazard ratio 1.7, CI 0.8–3.6, p = 0.1). In patients who developed resistance to osimertinib with paired pre- and post-treatment tissue samples, acquired MTAP del was identified in nine of 69 patients (13%). A heavily pretreated patient with metastatic EGFR-mutant, MTAP-del NSCLC had a confirmed partial response to treatment with PRMT5 inhibitor monotherapy (BMS-986504).
Conclusions
MTAP dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, MTAP-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.
MTAP（甲基硫腺苷磷酸化酶）缺失（dels）在非小细胞肺癌（nsclc）的一个亚群中与CDKN2A缺失一起发生。这些缺失与几种肿瘤类型的低生存率相关，并且它们可能通过合成致死性被PRMT5和MAT2A抑制剂靶向。它们与包括EGFR在内的致癌驱动因素的共同发生尚未得到充分研究。方法：我们分析了4926例使用MSK-IMPACT（下一代测序面板）测序的非小细胞肺癌肿瘤，并使用基于拷贝数的方法检查MTAP dels的发生率。结果：4926例NSCLC肿瘤中有475例（10%）存在MTAP模型。在258例IV期MTAP-del NSCLC肿瘤中，214例（83%）也有共同发生的致癌驱动改变，其中123例（48%）伴有EGFR突变。基线MTAP缺失与更短的奥西替尼单药停药时间相关（19.0个月vs 24.9个月，HR 1.8, CI 1.02 - 3.15， P=0.01），但对总生存期没有统计学意义（38.4个月vs 40.5个月，HR 1.7, CI 0.8 - 3.6， P=0.1）。在对奥希替尼产生耐药的患者中，9/69患者（13%）发现获得性MTAP del。一名经过大量预处理的转移性egfr突变MTAP-del NSCLC患者对PRMT5抑制剂单药治疗（BMS-986504）有部分缓解。结论：MTAP模型经常与致癌驱动改变共同发生，并可在奥西替尼耐药时发生。一名致癌驱动基因阳性的MTAP-del非小细胞肺癌患者对PRMT5抑制剂治疗有部分反应。这项工作可以为PRMT5和MAT2A抑制剂的未来试验提供信息。
{"title":"Clinical Significance of MTAP Deletions and Their Overlap With Concurrent Oncogenic Driver Alterations Including EGFR in NSCLC","authors":"Jessica S. Ross MD , Rohit Thummalapalli MD , Christopher A. Febres-Aldana MD , Daniel Muldoon MPH , Christina Falcon MPH , Amanda Pupo MA , Noura J. Choudhury MD , Guillherme Harada MD , Soo-Ryum Yang MD , Scott Eckert PhD , Francis M. Bodd MS , Jennifer L. Sauter MD , Chaitanya Bandlamudi PhD , Michael Berger PhD , Mark Y. Jeng MD, PhD , Michael Offin MD , Alexander Drilon MD , Mark G. Kris MD , Mark M. Awad MD, PhD , Helena Yu MD , Kathryn C. Arbour MD","doi":"10.1016/j.jtho.2025.11.010","DOIUrl":"10.1016/j.jtho.2025.11.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Methylthioadenosine phosphorylase (<em>MTAP</em>) deletions (dels) occur with <em>CDKN2A</em> dels in a subset of NSCLCs. These deletions have been associated with inferior survival in several tumor types, and they may be targetable by PRMT5 and MAT2A inhibitors through synthetic lethality. Their co-occurrence with oncogenic drivers including <em>EGFR</em> is underexplored.</div></div><div><h3>Methods</h3><div>We analyzed 4926 NSCLC tumors sequenced with MSK-IMPACT, a next-generation sequencing panel, and evaluated the incidence of <em>MTAP</em> dels with a copy number–based approach.</div></div><div><h3>Results</h3><div>Of 4926 NSCLC tumors, 475 (10%) harbored an <em>MTAP</em> del. Among 258 stage IV <em>MTAP</em>-del NSCLC tumors, 214 (83%) also had a co-occurring oncogenic driver alteration, including 123 (48%) with <em>EGFR</em> mutations. Baseline <em>MTAP</em> del was associated with shorter time to osimertinib monotherapy discontinuation (19.0 versus 24.9 mo, hazard ratio 1.8, confidence interval 1.02–3.15, <em>p</em> = 0.01) but did not statistically significantly affect overall survival (38.4 versus 40.5 mo, hazard ratio 1.7, CI 0.8–3.6, <em>p</em> = 0.1). In patients who developed resistance to osimertinib with paired pre- and post-treatment tissue samples, acquired <em>MTAP</em> del was identified in nine of 69 patients (13%). A heavily pretreated patient with metastatic <em>EGFR-</em>mutant, <em>MTAP-</em>del NSCLC had a confirmed partial response to treatment with PRMT5 inhibitor monotherapy (BMS-986504).</div></div><div><h3>Conclusions</h3><div><em>MTAP</em> dels frequently co-occur with oncogenic driver alterations and can develop at time of osimertinib resistance. A patient with oncogenic driver-positive, <em>MTAP</em>-del NSCLC had a partial response to PRMT5 inhibitor treatment. This work could inform future trials of PRMT5 and MAT2A inhibitors.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103520"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-03-04DOI: 10.1016/S1556-0864(26)00056-0
{"title":"Acknowledgment of Reviewers","authors":"","doi":"10.1016/S1556-0864(26)00056-0","DOIUrl":"10.1016/S1556-0864(26)00056-0","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103602"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147387710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-10-21DOI: 10.1016/j.jtho.2025.10.008
Igor Odintsov MD , Mark M. Hammer MD , Biagio Ricciuti MD , Federica Pecci MD , Mark M. Awad MD, PhD , Paul F. Dellaripa MD , Lynette M. Sholl MD
Introduction
Systemic sclerosis (SSc) is a chronic connective tissue disease associated with a significantly elevated and disproportionate risk of developing NSCLC, yet the underlying molecular drivers remain poorly understood. Specifically, it is unclear how these tumors fit within the established molecular paradigms of lung cancer, particularly in relation to the patient's smoking status and its associated genomics. Here, we investigated the genomics of NSCLC in patients with SSc and other connective tissue diseases associated with interstitial lung disease (ILD).
Methods
We retrospectively identified patients with SSc (n = 27) and other inflammatory ILD-associated NSCLC (n = 10) who underwent tumor genomic profiling. We collected clinical data (smoking, ILD features) and analyzed genomic alterations, tumor mutational burden, and mutational signatures, comparing them to a large NSCLC cohort.
Results
ILD (mostly nonspecific interstitial pneumonia) was present in all SSc never/light smokers but relatively infrequent in moderate/heavy smokers (p = 0.0016). NSCLC in SSc never and light smokers (n = 16) demonstrated a significant lack of canonical driver alterations enriched in never-smokers (mutations in EGFR or ERBB2 and oncogenic fusions) compared with non-SSc counterparts (0/16 versus 474/1255, p = 0.004) Conversely, TP53 mutations were enriched in this population (12/16, 75% versus 639/1394, 45.8%; p = 0.038). KRAS mutations were found in seven of 27 patients and were identified in patients with never, light and moderate smoking history. NSCLC from never and light smokers with SSc had enrichment of APOBEC-attributable variants versus non-SSc controls (55% increase, p = 0.02). Similar genomic findings were noted in a cohort of NSCLC arising in patients with other inflammatory ILD.
Conclusion
NSCLC in SSc and other inflammatory ILD, particularly in never and light smokers, displays distinct genomics: paucity of targetable drivers, frequent TP53 alterations, and APOBEC signature enrichment. This suggests a unique pathogenesis linked to chronic inflammation/autoimmunity, affecting therapeutic strategies.
{"title":"The Genomic Landscape of NSCLC in Systemic Sclerosis Reveals Frequent TP53 Mutations and a Paucity of Actionable Oncogenes","authors":"Igor Odintsov MD , Mark M. Hammer MD , Biagio Ricciuti MD , Federica Pecci MD , Mark M. Awad MD, PhD , Paul F. Dellaripa MD , Lynette M. Sholl MD","doi":"10.1016/j.jtho.2025.10.008","DOIUrl":"10.1016/j.jtho.2025.10.008","url":null,"abstract":"<div><h3>Introduction</h3><div>Systemic sclerosis (SSc) is a chronic connective tissue disease associated with a significantly elevated and disproportionate risk of developing NSCLC, yet the underlying molecular drivers remain poorly understood. Specifically, it is unclear how these tumors fit within the established molecular paradigms of lung cancer, particularly in relation to the patient's smoking status and its associated genomics. Here, we investigated the genomics of NSCLC in patients with SSc and other connective tissue diseases associated with interstitial lung disease (ILD).</div></div><div><h3>Methods</h3><div>We retrospectively identified patients with SSc (n = 27) and other inflammatory ILD-associated NSCLC (n = 10) who underwent tumor genomic profiling. We collected clinical data (smoking, ILD features) and analyzed genomic alterations, tumor mutational burden, and mutational signatures, comparing them to a large NSCLC cohort.</div></div><div><h3>Results</h3><div>ILD (mostly nonspecific interstitial pneumonia) was present in all SSc never/light smokers but relatively infrequent in moderate/heavy smokers (<em>p</em> = 0.0016). NSCLC in SSc never and light smokers (<em>n</em> = 16) demonstrated a significant lack of canonical driver alterations enriched in never-smokers (mutations in <em>EGFR</em> or <em>ERBB2</em> and oncogenic fusions) compared with non-SSc counterparts (0/16 versus 474/1255, <em>p</em> = 0.004) Conversely, <em>TP53</em> mutations were enriched in this population (12/16, 75% versus 639/1394, 45.8%; <em>p</em> = 0.038). <em>KRAS</em> mutations were found in seven of 27 patients and were identified in patients with never, light and moderate smoking history. NSCLC from never and light smokers with SSc had enrichment of APOBEC-attributable variants versus non-SSc controls (55% increase, <em>p</em> = 0.02). Similar genomic findings were noted in a cohort of NSCLC arising in patients with other inflammatory ILD.</div></div><div><h3>Conclusion</h3><div>NSCLC in SSc and other inflammatory ILD, particularly in never and light smokers, displays distinct genomics: paucity of targetable drivers, frequent <em>TP53</em> alterations, and APOBEC signature enrichment. This suggests a unique pathogenesis linked to chronic inflammation/autoimmunity, affecting therapeutic strategies.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"21 3","pages":"Article 103501"},"PeriodicalIF":20.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号